| 1. |
- Lankinen, Maria, et al.
(author)
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Effects of whole grain, fish and bilberries on serum metabolic profile and lipid transfer protein activities : a randomized trial (Sysdimet)
- 2014
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In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:2
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Journal article (peer-reviewed)abstract
- OBJECTIVE: We studied the combined effects of wholegrain, fish and bilberries on serum metabolic profile and lipid transfer protein activities in subjects with the metabolic syndrome.METHODS: Altogether 131 subjects (40-70 y, BMI 26-39 kg/m(2)) with impaired glucose metabolism and features of the metabolic syndrome were randomized into three groups with 12-week periods according to a parallel study design. They consumed either: a) wholegrain and low postprandial insulin response grain products, fatty fish 3 times a week, and bilberries 3 portions per day (HealthyDiet), b) wholegrain and low postprandial insulin response grain products (WGED), or c) refined wheat breads as cereal products (Control). Altogether 106 subjects completed the study. Serum metabolic profile was studied using an NMR-based platform providing information on lipoprotein subclasses and lipids as well as low-molecular-weight metabolites.RESULTS: There were no significant differences in clinical characteristics between the groups at baseline or at the end of the intervention. Mixed model analyses revealed significant changes in lipid metabolites in the HealthyDiet group during the intervention compared to the Control group. All changes reflected increased polyunsaturation in plasma fatty acids, especially in n-3 PUFAs, while n-6 and n-7 fatty acids decreased. According to tertiles of changes in fish intake, a greater increase of fish intake was associated with increased concentration of large HDL particles, larger average diameter of HDL particles, and increased concentrations of large HDL lipid components, even though total levels of HDL cholesterol remained stable.CONCLUSIONS: The results suggest that consumption of diet rich in whole grain, bilberries and especially fatty fish causes changes in HDL particles shifting their subclass distribution toward larger particles. These changes may be related to known protective functions of HDL such as reverse cholesterol transport and could partly explain the known protective effects of fish consumption against atherosclerosis.TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov NCT00573781.
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| 2. |
- Marklund, Matti, et al.
(author)
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A Dietary Biomarker Approach Captures Compliance and Cardiometabolic Effects of a Healthy Nordic Diet in Individuals with Metabolic Syndrome.
- 2014
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In: Journal of Nutrition. - : Elsevier BV. - 1541-6100 .- 0022-3166. ; 144:10, s. 1642-1649
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Journal article (peer-reviewed)abstract
- Assessment of compliance with dietary interventions is necessary to understand the observed magnitude of the health effects of the diet per se. To avoid reporting bias, different dietary biomarkers (DBs) could be used instead of self-reported data. However, few studies investigated a combination of DBs to assess compliance and its influence on cardiometabolic risk factors. The objectives of this study were to use a combination of DBs to assess compliance and to investigate how a healthy Nordic diet (ND) influences cardiometabolic risk factors in participants with high apparent compliance compared with the whole study population. From a recently conducted isocaloric randomized trial, SYSDIET (Systems Biology in Controlled Dietary Interventions and Cohort Studies), in 166 individuals with metabolic syndrome, several DBs were assessed to reflect different key components of the ND: canola oil (serum phospholipid α-linolenic acid), fatty fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], vegetables (plasma β-carotene), and whole grains (plasma alkylresorcinols). High-fat dairy intake (expectedly low in the ND) was reflected by serum pentadecanoic acid. All participants with biomarker data (n = 154) were included in the analyses. Biomarkers were combined by using a biomarker rank score (DB score) and principal component analysis (PCA). The DB score was then used to assess compliance. During the intervention, median concentrations of alkylresorcinols, α-linolenic acid, EPA, and DHA were >25% higher in the ND individuals compared with the controls (P < 0.05), whereas median concentrations of pentadecanoic acid were 14% higher in controls (P < 0.05). Median DB score was 57% higher in the ND compared with controls (P < 0.001) during the intervention, and participants were ranked similarly by DB score and PCA score. Overall, estimates of group difference in cardiometabolic effects generally appeared to be greater among compliant participants than in the whole study population (e.g., estimates of treatment effects on blood pressure and lipoproteins were ∼1.5- to 2-fold greater in the most compliant participants), suggesting that poor compliance attenuated the dietary effects. With adequate consideration of their limitations, DB combinations (e.g., DB score) could be useful for assessing compliance in intervention studies investigating cardiometabolic effects of healthy dietary patterns. The study was registered at clinicaltrials.gov as NCT00992641.
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| 3. |
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| 4. |
- Brader, Lea, et al.
(author)
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Effects of a healthy Nordic diet on plasma 25-hydroxyvitamin D concentration in subjects with metabolic syndrome: a randomized, placebo-controlled trial (SYSDIET)
- 2014
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In: European Journal of Nutrition. - : Springer Science and Business Media LLC. - 1436-6215 .- 1436-6207. ; 53:4, s. 1123-1134
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Journal article (peer-reviewed)abstract
- At northern latitudes, vitamin D is not synthesized endogenously during winter, causing low plasma 25-hydroxyvitamin D (25(OH)D) concentrations. Therefore, we evaluated the effects of a healthy Nordic diet based on Nordic nutrition recommendations (NNR) on plasma 25(OH)D and explored its dietary predictors. In a Nordic multi-centre trial, subjects (n = 213) with metabolic syndrome were randomized to a control or a healthy Nordic diet favouring fish (a parts per thousand yen300 g/week, including a parts per thousand yen200 g/week fatty fish), whole-grain products, berries, fruits, vegetables, rapeseed oil and low-fat dairy products. Plasma 25(OH)D and parathyroid hormone were analysed before and after 18- to 24-week intervention. At baseline, 45 % had vitamin D inadequacy (< 50 nmol/l), whereas 8 % had deficiency (< 25 nmol/l). Dietary vitamin D intake was increased by the healthy Nordic diet (P < 0.001). The healthy Nordic and the control diet reduced the prevalence of vitamin D inadequacy by 42 % (P < 0.001) and 19 % (P = 0.002), respectively, without between-group difference (P = 0.142). Compared with control, plasma 25(OH)D (P = 0.208) and parathyroid hormone (P = 0.207) were not altered by the healthy Nordic diet. Predictors for 25(OH)D were intake of vitamin D, eicosapentaenoic acids (EPA), docosahexaenoic acids (DHA), vitamin D supplement, plasma EPA and plasma DHA. Nevertheless, only vitamin D intake and season predicted the 25(OH)D changes. Consuming a healthy Nordic diet based on NNR increased vitamin D intake but not plasma 25(OH)D concentration. The reason why fish consumption did not improve vitamin D status might be that many fish are farmed and might contain little vitamin D or that frying fish may result in vitamin D extraction. Additional ways to improve vitamin D status in Nordic countries may be needed.
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| 5. |
- Damdimopoulou, Pauliina, et al.
(author)
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A single dose of enterolactone activates estrogen signaling and regulates expression of circadian clock genes in mice.
- 2011
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In: The Journal of nutrition. - : Elsevier BV. - 1541-6100 .- 0022-3166. ; 141:9, s. 1583-9
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Journal article (peer-reviewed)abstract
- Enterolactone (EL) is an enterolignan produced by gut microbiota from dietary plant lignans. Epidemiological and experimental studies suggest that EL and plant lignans may reduce the risk of breast and prostate cancer as well as cardiovascular disease. These effects are thought to at least in part involve modulation of estrogen receptor activity. Surprisingly little is known about the in vivo estrogenicity of EL. In the present study, we investigated the target tissues of EL, the genes affected by EL treatment, and the response kinetics. Following a single dose of EL, luciferase was significantly induced in reproductive and nonreproductive tissues of male and female 3xERE-luciferase mice, indicating estrogen-like activity. Microarray analysis revealed that EL regulated the expression of only 1% of 17β-estradiol target genes in the uterus. The majority of these genes were traditional estrogen target genes, but also members of the circadian signaling pathway were affected. Kinetic analyses showed that EL undergoes rapid phase II metabolism and is efficiently excreted. In vivo imaging demonstrated that the estrogen response followed similar, fast kinetics. We conclude that EL activates estrogen signaling in both male and female mice and that the transient responses may be due to the fast metabolism of the compound. Lastly, EL may represent a link among diet, gut microbiota, and circadian signaling.
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| 6. |
- Elo, Teresa D., et al.
(author)
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Stromal Activation Associated with Development of Prostate Cancer in Prostate-Targeted Fibroblast Growth Factor 8b Transgenic Mice
- 2010
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In: Neoplasia. - : Elsevier BV. - 1522-8002 .- 1476-5586. ; 12:11, s. 94-915
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Journal article (peer-reviewed)abstract
- Expression of fibroblast growth factor 8 (FGF-8) is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG) mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelial morphology progressing from atypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN) lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation.
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| 7. |
- Elo, Teresa, et al.
(author)
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Fibroblast Growth Factor 8b Causes Progressive Stromal and Epithelial Changes in the Epididymis and Degeneration of the Seminiferous Epithelium in the Testis of Transgenic Mice
- 2012
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In: Biology of Reproduction. - : Oxford University Press (OUP). - 1529-7268 .- 0006-3363. ; 86:5, s. 157-157
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Journal article (peer-reviewed)abstract
- Transgenic (Tg) mice expressing human fibroblast growth factor 8b (FGF8-b) under the probasin promoter (Tg [Pbsn-FGF8] L2-L5Elo; hereafter referred to as FGF8-b-Tg) were shown to produce FGF8-b at high levels in the prostate and epididymis and at lower levels in the testis. The present study examined the effects of FGF8-b expression on the epididymis and testis. In old (age, >6 mo) FGF8-b-Tg mice, epididymides were frequently enlarged, with epithelial and stromal hypercellularity progressing upon aging to epithelial dysplasia and malignant transformation of stroma. In addition, oligospermia, dilatation of the duct, and inflammation were frequently observed in the epididymides. In association with the epididymal changes, some FGF8-b-Tg mice presented a degenerative seminiferous epithelium of the testis. Consistent with this observation, infertile males were found in two FGF8-b-Tg mouse lines. Masson trichrome staining and immunohistochemical analysis of smooth muscle actin, laminin, and androgen receptor revealed that changes in the epididymal stroma closely resembled those previously found in the prostates of the FGF8-b-Tg mice. Genes previously found to be upregulated in the prostate of FGF8-b-Tg mice, such as osteopontin (Spp1) connective tissue growth factor (Ctgf), apolipoprotein D (Apod), and FGF receptor 1c (Fgfr1-c), were also upregulated in the epididymides, suggesting that similar molecular mechanisms were active in both tissues. However, unlike in the prostate, the changes in the epididymal epithelium of the FGF8-b-Tg mice did not progress into invasive carcinoma. The results suggest that prolonged and enhanced FGF signaling induces dramatic changes in the epididymis and testis that lead to infertility in a portion of the FGF8-b-Tg males.
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| 8. |
- Gonzalez, Betina, et al.
(author)
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Endogenously elevated androgens alter the developmental programming of the hypothalamic-pituitary axis in male mice.
- 2011
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In: Molecular and cellular endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 332:1-2, s. 78-87
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Journal article (peer-reviewed)abstract
- Transgenic male mice that express human chorionic gonadotropin (hCG) α and β subunits constitutively hypersecrete hCG and produce elevated levels of androgens. The aim of this study was to characterize the hypothalamic-pituitary function of these transgenic (hCGαβ+) males by focusing on FSH regulation. Serum FSH levels and pituitary mRNA expression of Fshb, Lhb, Cga, Gnrhr and Esr1 were reduced, whereas Fst expression was increased in prepubertal hCGαβ+ males as compared with wild-type. In the hypothalamus, Cyp19a1 expression, GnRH concentration and ex-vivo GnRH pulsatility were elevated in prepubertal hCGαβ+ mice, whereas Kiss1 expression was decreased prepubertally and Gad67 expression was elevated neonatally. The effect of androgens on the developmental programming of the hypothalamic-pituitary axis of hCGαβ+ males was evaluated by perinatal and prepubertal antiandrogen (flutamide) administration. Our studies identified a critical window between gestational day 18 and postnatal day 14, during which chronically elevated androgens and/or their locally produced metabolites activate the hypothalamus and concomitantly shut-down the gonadotropin axis.
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| 9. |
- Grimaldi, Giulia, et al.
(author)
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Down-regulation of the histone methyltransferase EZH2 contributes to the epigenetic programming of decidualizing human endometrial stromal cells.
- 2011
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In: Molecular endocrinology (Baltimore, Md.). - : The Endocrine Society. - 1944-9917 .- 0888-8809. ; 25:11, s. 1892-903
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Journal article (peer-reviewed)abstract
- Differentiation of human endometrial stromal cells (HESC) into decidual cells represents a highly coordinated process essential for embryo implantation. We show that decidualizing HESC down-regulate the histone methyltransferase enhancer of Zeste homolog 2 (EZH2), resulting in declining levels of trimethylation of histone 3 on lysine 27 (H3K27me3) at the proximal promoters of key decidual marker genes PRL and IGFBP1. Loss of H3K27me3 was associated with a reciprocal enrichment in acetylation of the same lysine residue, indicating active remodeling from repressive to transcriptionally permissive chromatin. Chromatin immunoprecipitation coupled with DNA microarray analysis demonstrated that decidualization triggers genome-wide changes in H3K27me3 distribution that only partly overlap those observed upon EZH2 knockdown in undifferentiated HESC. Gene ontology revealed that gain of the repressive H3K27me3 mark in response to decidualization and upon EZH2 knockdown in undifferentiated cells was enriched at the promoter regions of genes involved in transcriptional regulation and growth/cell proliferation, respectively. However, loss of the H3K27me3 mark (indicating increased chromatin accessibility) in decidualizing cells and upon EZH2 knockdown occurred at selective loci enriched for genes functionally implicated in responses to stimulus. In agreement, EZH2 knockdown in undifferentiated HESC was sufficient to augment the induction of decidual marker genes in response to cyclic AMP and progesterone signaling. Thus, loss of EZH2-dependent methyltransferase activity in the endometrium is integral to the process of chromatin remodeling that enables the transition from a proliferative to a decidual phenotype in response to differentiation cues.
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| 10. |
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| 11. |
- Horimoto, Yoshiya, et al.
(author)
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ERβ1 represses FOXM1 expression through targeting ERα to control cell proliferation in breast cancer.
- 2011
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In: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 179:3, s. 1148-56
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Journal article (peer-reviewed)abstract
- In this study, we investigated the effects of ectopic estrogen receptor (ER)β1 expression in breast cancer cell lines and nude mice xenografts and observed that ERβ1 expression suppresses tumor growth and represses FOXM1 mRNA and protein expression in ERα-positive but not ERα-negative breast cancer cells. Furthermore, a significant inverse correlation exists between ERβ1 and FOXM1 expression at both protein and mRNA transcript levels in ERα-positive breast cancer patient samples. Ectopic ERβ1 expression resulted in decreased FOXM1 protein and mRNA expression only in ERα-positive but not ERα-negative breast carcinoma cell lines, suggesting that ERβ1 represses ERα-dependent FOXM1 transcription. Reporter gene assays showed that ERβ1 represses FOXM1 transcription through an estrogen-response element located within the proximal promoter region that is also targeted by ERα. The direct binding of ERβ1 to the FOXM1 promoter was confirmed by chromatin immunoprecipitation analysis, which also showed that ectopic expression of ERβ1 displaces ERα from the endogenous FOXM1 promoter. Forced expression of ERβ1 promoted growth suppression in MCF-7 cells, but the anti-proliferative effects of ERβ1 could be overridden by overexpression of FOXM1, indicating that FOXM1 is an important downstream target of ERβ1 signaling. Together, these findings define a key anti-proliferative role for ERβ1 in breast cancer development through negatively regulating FOXM1 expression.
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| 12. |
- Huhtinen, Kaisa, et al.
(author)
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Endometrial and Endometriotic Concentrations of Estrone and Estradiol Are Determined by Local Metabolism Rather than Circulating Levels.
- 2012
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 97:11, s. 4228-35
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Journal article (peer-reviewed)abstract
- Context:Aberrant estrogen synthesis and metabolism have been suggested to increase local estradiol (E2) concentration in endometriosis and thus to promote the growth of the lesions. However, tissue estrogen concentrations within the endometrium and different types of endometriosis lesions have not been described.Objective:The aim of the study was to evaluate local E2 and estrone (E1) concentrations in the endometrium and different types of endometriosis lesions, and to correlate them with the expression of estrogen-metabolizing enzymes.Patients:Patients with endometriosis (n = 60) and healthy controls (n = 16) participated in the study.Main Outcome Measures:We measured serum and tissue concentrations of E2 and E1 as well as mRNA expression of the estrogen-metabolizing enzymes.Results:Endometrial or endometriotic intratissue E2 concentrations did not reflect the corresponding serum levels. In the proliferative phase, endometrial E2 concentration was five to eight times higher than in the serum, whereas in the secretory phase the E2 concentration was about half of that in the serum. Accordingly, a markedly higher E2/E1 ratio was observed in the endometrium at the proliferative phase compared with the secretory phase. In the endometriosis lesions, E2 levels were predominating over those of E1 throughout the menstrual cycle. Among the hydroxysteroid (17β) dehydrogenase (HSD17B) enzymes analyzed, HSD17B2 negatively correlated with the E2 concentration in the endometrium, and HSD17B6 was strongly expressed, especially in the deep lesions.Conclusions:Endometrial or endometriotic tissue E2 concentrations are actively regulated by local estrogen metabolism in the tissue. Thus, the inhibition of local E2 synthesis is a valid, novel approach to reduce local E2-dependent growth of endometriotic tissue.
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| 13. |
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| 14. |
- Jonsdottir, Svandis Erna, et al.
(author)
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Adherence to the Nordic Nutrition Recommendations in a Nordic population with metabolic syndrome : high salt consumption and low dietary fibre intake (The SYSDIET study)
- 2013
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In: Food & Nutrition Research. - : SNF Swedish Nutrition Foundation. - 1654-6628 .- 1654-661X. ; 57, s. UNSP 21391-
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Research review (peer-reviewed)abstract
- Background: The Nordic countries collaborate in setting recommendations for intake of nutrients by publishing the Nordic Nutrition Recommendations (NNR). Studies exploring how well the Nordic population adheres to the NNR are limited and none are available for the metabolic syndrome (MetS) subgroup. Individuals with MetS are a large part of the adult Nordic population and their diet's nutritional quality is of great importance as it can affect the progression of MetS. Objective: To evaluate nutritional intake in a cohort of Nordic adults with MetS or MetS risk factors and their adherence to the NNR. Design: A multi-centre study was carried out in six centres in four Nordic countries (SYSDIET CoE). Participants (n = 175) were 30-65 years of age, with BMI 27-38 kg/m(2) and had at least two criteria for MetS. The NNR was used to evaluate the baseline nutrient intake calculated from the participants' 4-day food diaries using national nutrient databases. Results: Less than 20% of participants consumed <= 10 E% from saturated fat as recommended in the NNR. Recommended intake (RI) of polyunsaturated fat was met by approximately one-third of participants. Only 20% of men and 26% of women met the RI of dietary fibre. Intake below the defined lower intake level of 2.5 mu g/day for vitamin D was observed in nearly 20% of participants. The daily median intake of salt was 8.8 g for men and 6.7 g for women. Conclusion: Dietary quality of this Nordic population with Mets or MetS risk factors is unsatisfactory and characterised by high intakes of SFA and sodium and low intakes of PUFA and dietary fibre. Vitamin D intake was below RI level in a large part of the population. Authorities in the Nordic countries are encouraged to develop intervention programmes for high-risk groups.
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| 15. |
- Joukamo, Laura, et al.
(author)
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Rasvainen kala muokkaa HDL-hiukkaskokoa ja lipidipitoisuuksia [Fatty fish modifies HDL particle size and lipid concentrations]
- 2013
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In: Duodecim. - : Duodecim. - 0012-7183 .- 2242-3281. ; 129:24, s. 2661-2670
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Journal article (peer-reviewed)abstract
- BACKGROUND: We investigated with 1HNMR-spectroscopy the effects of habitual fatty fish intake on serum lipiprotein profiles in persons with features of metabolic syndrome.MATERIAL AND METHODS: The participants (n = 105) were randomized into three diet intervention groups. The groups were given different dietary instructions.RESULTS: Increased intake of fatty fish had a significant (p < 0.05) increasing effect on the amount of large HDL-lipoprotein subclasses and their lipids.CONCLUSIONS: Frequent intake of fatty fish may have beneficial effects on HDL-metabolism beyond that assumed to be related to its serum concentrations.
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| 16. |
- Keski-Rahkonen, Pekka, et al.
(author)
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Fast and sensitive liquid chromatography-mass spectrometry assay for seven androgenic and progestagenic steroids in human serum.
- 2011
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In: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 127:3-5, s. 396-404
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Journal article (peer-reviewed)abstract
- A fast and sensitive LC-MS/MS method for the quantitative analysis of seven steroid hormones in 150 μl of human serum was developed and validated. The following compounds were included: 17α-hydroxypregnenolone, 17α-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, testosterone, pregnenolone, and progesterone. Individual stable isotope-labeled analogues were used as internal standards. Sample preparation was performed by liquid-liquid extraction, followed by oxime derivatization to improve the ionization efficiency of the analytes. In contrast to the common derivatization-based methods, the reaction was incorporated into the sample preparation process and the only additional step due to the derivatization was a short heating of the autosampler vials before the sample injection. Chromatographic separation was achieved on a reversed-phase column using a methanol-water gradient. For the analyte detection, a triple quadrupole instrument with electrospray ionization was used. Total run time was 7.0 min and the lower limits of quantification were in the range of 0.03-0.34 nM (0.01-0.10 ng/ml), depending on the analyte. The method was validated using human serum samples from both sexes and applied for the serum steroid profiling of endometriosis patients.
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| 17. |
- Knuuttila, M., et al.
(author)
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Castration Induces Up-Regulation of Intratumoral Androgen Biosynthesis and Androgen Receptor Expression in an Orthotopic VCaP Human Prostate Cancer Xenograft Model
- 2014
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In: American Journal of Pathology. - : Elsevier BV. - 0002-9440. ; 184:8, s. 2163-2173
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Journal article (peer-reviewed)abstract
- Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups. Serum prostate-specific antigen concentrations showed significant correlation with tumor volume. Castration-resistant tumors retained concentrations of intratumoral androgen (androstenedione, testosterone, and 5 alpha-dihydrotestosterone) at Levels similar to tumors growing in intact hosts. Accordingly, castration induced up-regulation of enzymes involved in androgen synthesis (CYP17A1, AKR1C3, and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. The AR antagonists enzalutamide (MDV3100) and ARN-509 suppressed PSA production of castration-resistant tumors, confirming the androgen dependency of these tumors. Taken together, the findings demonstrate that our VCaP xenograft model exhibits the key characteristics of clinical CRPC and thus provides a valuable tool for identifying druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.
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| 18. |
- Krutskikh, Anton, et al.
(author)
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Targeted inactivation of the androgen receptor gene in murine proximal epididymis causes epithelial hypotrophy and obstructive azoospermia.
- 2011
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In: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 152:2, s. 689-96
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Journal article (peer-reviewed)abstract
- The epithelial lining of the epididymal duct expresses the androgen receptor (Ar) along its entire length and undergoes rapid and profound degeneration when androgenic support is withdrawn. However, experiments involving orchidectomy with systemic testosterone replacement, and testicular efferent duct ligation, have indicated that structural and functional integrity of the initial segment cannot be maintained by circulating androgen alone, leaving the role of androgen in this epididymal zone unclear. We addressed this question in a mouse model with intact testicular output and selective Ar inactivation in the proximal epididymis by creating double-transgenic males carrying a conditional Ar(loxP) allele and expressing Cre recombinase under the promoter of Rnase10, a gene specifically expressed in proximal epididymis. At 20-25 d of life, on the onset of Rnase10 expression, Ar became selectively inactivated in the principal cells of proximal epididymis, resulting in epithelial hypoplasia and hypotrophy. Upon the subsequent onset of spermiation, epididymal obstruction ensued, with the consequent development of spermatic granulomata, back pressure-induced atrophy of the seminiferous epithelium, orchitis, and fibrosis of the testicular parenchyma. Consistent with these findings, the mice were infertile. When the effect of Ar knockout on gene expression in the proximal epididymis was compared with that of efferent duct ligation and orchidectomy, we identified genes specifically regulated by androgen, testicular efferent fluid, and both. Our findings demonstrate that the development and function of the epididymal initial segment is critically dependent on direct androgen regulation. The phenotype of the produced knockout mouse provides a novel model for obstructive azoospermia.
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| 19. |
- Laajala, Teemu D, et al.
(author)
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Improved statistical modeling of tumor growth and treatment effect in preclinical animal studies with highly heterogeneous responses in vivo.
- 2012
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In: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 18:16, s. 4385-96
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Journal article (peer-reviewed)abstract
- Preclinical tumor growth experiments often result in heterogeneous datasets that include growing, regressing, or stable growth profiles in the treatment and control groups. Such confounding intertumor variability may mask the true treatment effects especially when less aggressive treatment alternatives are being evaluated. Experimental design: We developed a statistical modeling approach in which the growing and poorly growing tumor categories were automatically detected by means of an expectation-maximization algorithm coupled within a mixed-effects modeling framework. The framework is implemented and distributed as an R package, which enables model estimation and statistical inference, as well as statistical power and precision analyses.
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| 20. |
- Lankinen, Maria, et al.
(author)
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Whole grain products, fish and bilberries alter glucose and lipid metabolism in a randomized, controlled trial : the Sysdimet study
- 2011
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In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 6:8
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Journal article (peer-reviewed)abstract
- BACKGROUND: Due to the growing prevalence of type 2 diabetes, new dietary solutions are needed to help improve glucose and lipid metabolism in persons at high risk of developing the disease. Herein we investigated the effects of low-insulin-response grain products, fatty fish, and berries on glucose metabolism and plasma lipidomic profiles in persons with impaired glucose metabolism.METHODOLOGY/PRINCIPAL FINDINGS: Altogether 106 men and women with impaired glucose metabolism and with at least two other features of the metabolic syndrome were included in a 12-week parallel dietary intervention. The participants were randomized into three diet intervention groups: (1) whole grain and low postprandial insulin response grain products, fatty fish three times a week, and bilberries three portions per day (HealthyDiet group), (2) Whole grain enriched diet (WGED) group, which includes principally the same grain products as group (1), but with no change in fish or berry consumption, and (3) refined wheat breads (Control). Oral glucose tolerance, plasma fatty acids and lipidomic profiles were measured before and after the intervention. Self-reported compliance with the diets was good and the body weight remained constant. Within the HealthyDiet group two hour glucose concentration and area-under-the-curve for glucose decreased and plasma proportion of (n-3) long-chain PUFAs increased (False Discovery Rate p-values <0.05). Increases in eicosapentaenoic acid and docosahexaenoic acid associated curvilinearly with the improved insulin secretion and glucose disposal. Among the 364 characterized lipids, 25 changed significantly in the HealthyDiet group, including multiple triglycerides incorporating the long chain (n-3) PUFA.CONCLUSIONS/SIGNIFICANCE: The results suggest that the diet rich in whole grain and low insulin response grain products, bilberries, and fatty fish improve glucose metabolism and alter the lipidomic profile. Therefore, such a diet may have a beneficial effect in the efforts to prevent type 2 diabetes in high risk persons.TRIAL REGISTRATION: ClinicalTrials.gov NCT00573781.
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| 21. |
- Magnusdottir, O. K., et al.
(author)
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Plasma alkylresorcinols C17:0/C21:0 ratio, a biomarker of relative whole-grain rye intake, is associated to insulin sensitivity : a randomized study
- 2014
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In: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 0954-3007 .- 1476-5640. ; 68:4, s. 453-458
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Journal article (peer-reviewed)abstract
- BACKGROUND/OBJECTIVES: Few studies have used biomarkers of whole-grain intake to study its relation to glucose metabolism. We aimed to investigate the association between plasma alkylresorcinols (AR), a biomarker of whole-grain rye and wheat intake, and glucose metabolism in individuals with metabolic syndrome (MetS). SUBJECTS/METHODS: Participants were 30-65 years of age, with body mass index 27-40 kg/m(2) and had MetS without diabetes. Individuals were recruited through six centers in the Nordic countries and randomized to a healthy Nordic diet (ND, n=96), rich in whole-grain rye and wheat, or a control diet (n=70), for 18-24 weeks. In addition, associations between total plasma AR concentration and C17:0/C21:0 homolog ratio as an indication of the relative whole-grain rye intake, and glucose metabolism measures from oral glucose tolerance tests were investigated in pooled (ND + control) regression analyses at 18/24 weeks. RESULTS: ND did not improve glucose metabolism compared with control diet, but the AR C17:0/C21:0 ratio was inversely associated with fasting insulin concentrations (P=0.002) and positively associated with the insulin sensitivity indices Matsuda ISI (P=0.026) and disposition index (P=0.022) in pooled analyses at 18/24 weeks, even after adjustment for confounders. The AR C17:0/C21:0 ratio was not significantly associated with insulin secretion indices. Total plasma AR concentration was not related to fasting plasma glucose or fasting insulin at 18/24 weeks. CONCLUSIONS: The AR C17:0/C21:0 ratio, an indicator of relative whole-grain rye intake, is associated with increased insulin sensitivity in a population with MetS.
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| 22. |
- Magnusdottir, Ola Kally, et al.
(author)
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Plasma Alkylresorcinols Reflect Important Whole-Grain Components of a Healthy Nordic Diet
- 2013
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In: Journal of Nutrition. - : Elsevier BV. - 0022-3166 .- 1541-6100. ; 143:9, s. 1383-1390
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Journal article (peer-reviewed)abstract
- Biomarkers of dietary intake can be important tools in nutrition research. Our aim was to assess whether plasma alkylresorcinol (AR) and beta-carotene concentrations could be used as dietary biomarkers for whole-grain, fruits and vegetables in a healthy Nordic diet (ND). Participants (n = 166), 30-65 y with a body mass index of 27-40 kg/m(2) and two more features of metabolic syndrome (International Diabetes Federation definition, slightly modified), were recruited through six centers in the Nordic countries and randomly assigned to an ND or control diet for 18 or 24 wk, depending on study center. Plasma AR and beta-carotene were analyzed and nutrient intake calculated from 4-d food records. Median fiber intake increased in the ND group from 2.5 g/MJ at baseline to 4.1 g/MJ (P < 0.001) at end point (week 18 or 24), and median (IQR) fasting plasma total AR concentration increased from 73 (88) to 106 (108) nmol/L, or 45%, from baseline to end point (P < 0.001). The AR concentration was significantly higher in the ND group (P < 0.001) than in the control group at end point. beta-Carotene intake tended to increase in the ND group (P = 0.07), but the plasma beta-carotene concentration did not change significantly throughout the study and did not differ between the groups at follow-up. In conclusion, an ND resulted in higher dietary fiber intake and increased plasma total AR concentration compared with the control diet, showing that the total AR concentration might be a valid biomarker for an ND in which whole-grain wheat and rye are important components. No significant difference in plasma beta-carotene concentrations was observed between the ND and control groups, suggesting that beta-carotene may not be a sensitive enough biomarker of the ND.
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| 23. |
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| 24. |
- Movérare-Skrtic, Sofia, et al.
(author)
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Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
- 2014
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 20:11, s. 1279-88
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Journal article (peer-reviewed)abstract
- The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.
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| 25. |
- Poutanen, Juho, et al.
(author)
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Multi-link MIMO channel modeling using geometry-based approach
- 2012
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In: IEEE Transactions on Antennas and Propagation. - 0018-926X. ; 60:2, s. 587-596
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Journal article (peer-reviewed)abstract
- Geometry-based stochastic channel models (GSCMs) are extended to support multi-link simulations by applying the concept of common clusters. This novel approach aims to control the correlation between different links, inter-link correlation, by adjusting the amount of power simultaneously propagating via the same clusters in the different links. The behavior of common clusters is analyzed based on dual-link channel measurements, and a multi-link GSCM is developed based on common clusters. In addition, the effects that the common clusters have on inter-link correlation and on sum rate capacity are investigated based on simulations. Finally, comparison between simulations and measurements is done in order to indicate the validity of the proposed multi-link GSCM.
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